The goals of this project are to understand how the interactions between the transferring receptor (TfR) and transferrin (Tf) and the TfR and the hemochromatosis gene product regulate iron transport into cells. The long term goal of my research is to understand the structure and function of this important receptor. The uptake of iron into mammalian cells involves the binding of Tf to the TfR, followed by internalization of the receptor-Tf complex. Iron uptake is essential for cell division and as a result the TfR has been identified as a proliferation specific marker. It is present on rapidly dividing cells. The uptake of iron into the body and into cells is tightly controlled. Too little iron in mammals results in anemia and failure to thrive. Too much iron results in iron toxicity due to oxidative damage. Hereditary hemochromatosis is a disease of iron overload. Excess iron damages organs and results in liver failure, adult onset diabetes, arthritis and heart failure. It is the most common inherited disease in people of European descent affecting approximately 1 in 400 individuals. Recently the gene was identified and found to bind to the TfR. Key to understanding the regulation of iron uptake is understanding the interactions between the hemochromatosis gene product and between Tf and the TfR. The specific goals of this study application are: to map the interactions between these proteins; to determine how the TfR potentiates the release of iron in the endosome; to determine how the hemochromatosis gene product alters the interaction between Tf and the TfR; and finally to determine the limiting factors in the uptake of iron into cells.